This research project is to investigate the biochemical mechanisms of kepone- and mirex-induced neurotoxicity. There is ample evidence to suggest that neurological manifestations of toxicity of many chlorinated hydrocarbon pesticides are mediated through the central nervous system. Occupational exposure to kepone has resulted in a heretofore undescribed kepone-associated neurological syndrome. However, very little information is available regarding the biochemical mechanisms of kepone-induced neurological manifestations. Preliminary results of the P.I. are suggestive of disturbances in levels of neurotransmitters in the CNS of kepone treated symptomatic experimental animals. Therefore, it is proposed to use kepone and its close structural analog, mirex as models to explore the biochemical mechanism by which neurotoxicity is brought about by these chemicals. The research plan proposes (I) the systematic assessment of neurotoxicities produced by kepone and mirex and (II) studies on the biochemical mechanisms of action of kepone and mirex on the CNS. Specifically, we will study (1) the distribution and half-lives of kepone and mirex in plasma and brain; (2) the acute and chronic effects of kepone and mirex on the changes in neurotransmitter levels, synthesis, release, uptake turnover rates and their related enzymes; (3) c-AMP and c-GMP and their synthesizing enzymes in both acutely and chronically treated animals, and (4) three types of ATPase activities of the brain in both acute and chronic treated animals. Finally, based on the results obtained from the above studies we will confirm our biochemical data with pharmacological manipulations. Hopefully, this will lead us to a better understanding of the mechanisms underlying kepone and mirex induced neurotoxicity and thus provide a more rational basis for the treatment of human ailment due to accidental or occupational exposure to this class of neurotoxin.